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United States Patent |
5,017,664
|
Grasel
,   et al.
|
May 21, 1991
|
Biocompatible polyurethane devices wherein polyurethane is modified with
lower alkyl sulfonate and lower alkyl carboxylate
Abstract
Modified-polyurethane block copolymers and devices formed therefrom
demonstrate excellent biocompatibilty and improved physical and mechanical
properties. In a preferred embodiment, from about 5 to about 25 percent of
urethane hydrogen atoms are replaced with propyl sulfonate and propyl
carboxylate groups to provide the modified copolymer.
Inventors:
|
Grasel; Timothy G. (Madison, WI);
Cooper; Stuart L. (Madison, WI)
|
Assignee:
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Wisconsin Alumni Research Foundation (Madison, WI)
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Appl. No.:
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333991 |
Filed:
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April 5, 1989 |
Current U.S. Class: |
525/454; 528/49; 528/71; 604/266 |
Intern'l Class: |
C08G 018/82; C08G 018/87 |
Field of Search: |
525/454
528/49,71
604/266
|
References Cited
U.S. Patent Documents
3903032 | Sep., 1975 | Matsuda et al. | 528/71.
|
4237250 | Dec., 1980 | Dieterich | 525/454.
|
4276044 | Jun., 1981 | Dieterich | 528/71.
|
4303774 | Dec., 1981 | Machtkamp et al. | 528/71.
|
4503198 | Mar., 1985 | Miyai et al. | 528/71.
|
4579930 | Apr., 1986 | Kramer et al. | 528/71.
|
4670330 | Jun., 1987 | Ishiwata | 528/71.
|
4675361 | Jun., 1987 | Ward, Jr. | 525/454.
|
4689386 | Aug., 1987 | Chapman et al. | 528/71.
|
4831065 | May., 1989 | Pietsch et al. | 525/454.
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Other References
Lelah et al., "Polyether-Urethane Ionomers Surface Property/Ex Vivo Blood
Compatibility Relationships", J. Coll. Interf. Sci., 104, 422-439 (1985)
(Article I).
Lelah et al., "Ex Vivo Interactions and Surface Property Relationships of
Polyetherurethanes," J. Biomed. Mater. Res., 20 433-468 (1986) (Article
II).
Hwang et al., "Properties of Polyurethane Anioniomers: Ionization via
Bimolecular Nucleophilic Displacement of Urethane Hydrogen,", J. Macromol.
Sci.-Phys., B23, 154-174 (1984).
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Primary Examiner: Foelak; Morton
Assistant Examiner: Daley; Dennis R.
Attorney, Agent or Firm: Olson & Hierl
Goverment Interests
This invention was made with United States Government support awarded by
the National Institutes of Health (NIH), Grant Number: HL 24046. The
United States Government has certain rights in this invention.
Parent Case Text
This application is a division of application Ser. No. 057,546, filed June
3, 1987, now U.S. Pat. No. 4,880,883.
TECHNICAL FIELD OF THE INVENTION
This invention relates to polyurethanes and, in particular, to polyurethane
block copolymers which demonstrate excellent biocompatibility and improved
physical and mechanical properties.
BACKGROUND OF THE INVENTION
The properties of a polymer are of great importance in any application. For
biomedical polymers, the most important single property is probably
biocompatibility, which refers to the interactions of living body tissues,
compounds and fluids including blood with any implanted or contacting
polymeric material. Each system of polymer-body tissue interactions must
be studied individually in terms of polymer stability, general
tissue-fluid interactions and blood compatibility.
Polyurethane block copolymers have been proposed for use in
blood-contacting applications because of their generally excellent
physical properties and relatively good blood compatibility. Lelah and
Cooper, Polyurethanes in Medicine, CRC Press, Boca Raton, Fla. (1986). It
is desirable however, to further improve the blood compatibility of these
materials to allow their use in such demanding applications as
small-diameter vascular grafts, catheters, kidney dialyzers, cardiac
assist devices and the artificial heart.
Thrombus formation on polyurethanes and other blood-contacting biomaterials
can lead to occlusion of vascular grafts or catheters, and detachment
(embolization) of these thrombi may result in tissue damage or strokes.
Several approaches have been proposed for improving the blood
compatibility of blood-contacting biomaterials. One method involves the
preparation of a highly hydrophilic, mobile interface comprising materials
that appear "bland" to blood components. Merrill et al., Am. Soc. Artif.
Intern. Organs J., 6, 60 (1983). These "bland" materials may demonstrate a
reduced tendency for protein absorption and platelet adhesion.
Another method involves the introduction of highly hydrophobic groups to
the blood-contacting interface, either by using a highly hydrophobic
polymer such as silicone rubber or by grafting long alkyl chains to a
relatively hydrophilic material, such as a polyurethane block copolymer.
By using long-chain alkyl grafting methods, Eberhart and coworkers [Munro,
et al., Am. Soc. Artif. Intern. Organs J., 6, 65 (1983)] have improved the
blood compatibility of polyurethane block copolymers. Similar approaches
have resulted in the reduction of platelet and fibrinogen deposition in
canine ex vivo blood-contacting studies.
A third method involves incorporating ionic character into the polymer.
This approach may also result in a highly hydrophilic and mobile interface
which has a low driving force for protein adsorption and cell adhesion. In
fact, many researchers have used this approach in an attempt to provide a
surface that will initiate the anti-coagulant action of heparin, a highly
ionic mucopolysaccharide.
The electrical nature of a polymeric substrate is an important determinant
of interfacial energetics. Many components of mammalian blood, including
red blood cells, platelet surfaces, plasma proteins, and morula vascular
endothelium, are negatively charged at physiological pH. Thus, ionic
groups play an important, but not yet fully understood, role in
blood-material interactions.
Sawyer and Pate [Born, Ann. NY Acad. Sci., 201, 4 (1972)] demonstrated that
normal vascular endothelium is negatively charged and proposed that the
natural blood vessel is thromboresistant due to repulsion between negative
charges on the vessel wall and the blood components. Sawyer et al., Bull.
NY Acad. Med., 48, 235 (1972) also examined a number of metals and
demonstrated that relatively electronegative metals are less thrombogenic
than others. One study concluded that polymers with a negative zeta
potential, including an acrylic latex combined with a sulfonate detergent,
carboxyl cellulose and fluorinated silicones are relatively blood
compatible. (Rembaum et al., Polym. Prepr., 16, 191 (1975).
Negative charge by itself, however, is not sufficient to impart
thromboresistance to a material. Glass, for example, is a well-known
coagulant in spite of its relatively large negative zeta potential. In
studies of the blood compatibility of silicone rubber, Musolf et al., NIH
PB, 90, 666 (1969) found that carboxylation failed to improve the observed
blood compatibility. Hageman Factor (an intrinsic blood clotting factor)
has been shown to be activated by a variety of negatively charged
surfaces. Nossel et al., Nature, 221, 74 (1969). Thus, the mechanism of
action for a negatively-charged species such as heparin in coagulation
inhibition is believed to be much more complex than merely the action of
the negative charge.
It is well-known that plasma proteins are rapidly adsorbed when blood
contacts an artificial surface, and it is believed that this protein layer
influences the thrombogenicity of the surface. For example, the amount of
platelet activation appears to be strongly mediated by the adsorbed
protein layer. Park et al., J. Biomed. Mater. Res., 20, 589 (1986). The
degree of platelet spreading which is promoted by the surface and the
adsorbed protein layer is an important parameter for controlling the
thrombogenicity of the surface and has been found to affect the relative
amounts of proteins which adsorb at the interface. Weathersby et al., J.
Bioeng., 1, 395 (1977); Baszkin et al., J. Biomed. Mater. Res., 14, 393
(1980) and Van Dulm et al., J. Coll. Int. Sci., 91, 248 (1983).
More direct investigations of surface charge effects on protein adsorption
have been attempted, but conflicting results have been obtained. It has
been found, for example, that ionic character in itself has relatively
minor effects on protein adsorption when compared to other parameters.
Schmitt et al., J. Coll. Int. Sci., 92, 25 (1983); Morrissey et al., J.
Coll. Int. Sci., 56, 537 (1976) and Norde et al., J. Coll. Int. Sci., 66,
257 (1978). Van Dulm et al., J. Coll. Int. Sci., 56, 557 (1976) reported
that in one case albumin adsorption behavior differed markedly from other
situations, and relatively slow initial adsorption rates were observed in
the special case where both species were negatively charged.
It has also been demonstrated that polymers with carboxylate functional
groups interact with proteins in a different manner than those with
sulfonate groups. Bernfeld, P., "Interaction of Polyanions With Blood
Components", in The Amino Sugars, Balaz E. A. and Jeanloz, R. W. (eds.)
Academic Press, New York, 251-256 (1966) and Gelman et al., Biopolymers,
12, 541 (1973). Recent work by Fougnot et al., Biomaterials, 5, 89 (1984)
has shown that the binding of sulphamide and/or sulfonate groups to a
substrate produces surfaces with relatively high affinities for albumin,
thrombin and antithrombin. These substrates were shown to be relatively
blood-compatible when compared to other surfaces.
However, the effect of ionic character on protein adsorption and subsequent
thrombogenesis is still quite controversial. Muramatsu et al., J. Biomed.
Mater. Res., 17, 959 (1983) studied protein adsorption using static
adsorption methods to determine adsorption isotherms on artificial red
blood cell surfaces. It was determined that the surface negative charge of
the surfaces, as evidenced by the relative number of sulfonic acid groups
present, strongly affected the composition, molecular orientation, and/or
configuration of adsorbing plasma components. Fibrinogen and gammaglobulin
adsorption were particularly affected by surface charge.
The mechanism of heparin action has also been considered in anticoagulation
research. Heparin is a naturally-occurring mucopolysaccharide
anticoagulant. Its molecular weight ranges from below 10,000 to above
20,000, with the higher molecular weight fraction generally showing a
higher level of anti-coagulant activity. Ebert et al., "The Anticoagulant
Activity of Derivatized and Immobilized Heparins", in Biomaterials:
Interfacial Phenomena and Applications, Cooper, S. L. and Peppas, N. A.
(eds.), ACS Adv. in Chem. Services, 199, 161 (1982). The mechanisms by
which heparin exerts its anticoagulant function are not well-defined.
Ebert et al., id.; Jozefowicz et al., Pure and Appl. Chem., 56, 1335
(1984) and Olsson et al., Ann. NY Acad. Sci., 416, 525 (1984).
The most potent plasma inhibitor of the coagulation process is antithrombin
III (AT-III), which forms inactive stable complexes with serine-proteases
including clotting factors IIa, IXa, Xa, IXa and kallikrein. These
reactions are believed to be subject to catalysis by heparin and heparin
analogs which might be present in some subendothelial or endothelial
tissue. The generally accepted scheme is that heparin binds to AT-III and
greatly potentiates thrombin binding to AT-III binding sites in the
heparin AT-III complex. The complex not only binds to thrombin, but also
binds to every active serine protease in the intrinsic coagulation
pathway.
Lindsay et al., Trans. Am. Soc. Artif. Inter. Organs, 22, 292 (1976) cited
a number of conflicting reports on the action of heparin on platelets and
concluded that variations in experimental techniques probably account for
the many contradictory findings. Their own in vitro platelet retention
study indicated that heparin had two antagonistic effects in
platelet-foreign surface interactions. First, heparin in the blood was
found to act directly on platelets to increase their retention. Second,
the reduction of platelet adhesion to surfaces to which heparin was
ionically attached led to the conclusion that heparin acted on the foreign
surface, probably by competing for cationic sites. This suggests that
heparinized surfaces may be passivated, but the heparin may not be
performing its normal biological function.
It was found by Gott et al., Trans. Am. Soc. Artif. Inter. Organs, 10, 213
(1964) that heparin ionically bound to a polymer surface tends to result
in a decreased tendency for the surface to promote coagulation. Since that
time, the covalent and ionic binding of heparin and other anticoagulants
have been the subject of numerous studies. Jozefowicz et al., id. and
Olsson et al., id. review these studies. While ionically bound heparin has
demonstrated antithrombogenic characteristics, materials heparinized in
this manner have been effective only while they release the ionically
bound heparin into the bloodstream. This mechanism is not satisfactory for
long-term implantation. Van der Lei et al., Trans. Am. Soc. Artif. Intern.
Organs, 31, 107 (1985) found that ionically-bound heparin does not
increase patency in small diameter polyurethane vascular grafts.
Covalently-bonded heparin surfaces have been developed; and in most, but
not all cases [Hashimoto, K., Tokohu J. Exp. Med., 81, 93 (1963)], an
improvement in antithrombogenicity of the derivatized surfaces with
respect to the untreated surfaces has been shown. In agreement with the
foregoing discussion, it has been noted that the surfaces to which heparin
is covalently bound tend to activate platelets when exposed to blood or a
platelet suspension (Jozefowicz et al., id.). A surface modification of a
BIOMER polyurethane vascular graft involving covalently-bound heparin did
not result in decreased platelet or fibrinogen deposition in two canine ex
vivo experiments. Lelah M.D., Ph.D. Dissertation, Univ. of
Wisconsin-Madison (1984).
Recent results by Sharma et al., ACS Div. Polym. Mat. Sci. Eng. Prepr., 53,
423 (1985) indicated that some heparinization methods for polyurethanes
resulted in sharply increased fibrinogen adsorption from in vitro
competitive adsorption experiments, and also provided a dramatic decrease
in platelet adhesion from platelet-rich plasma. These investigators
attributed their findings to specific interactions between the platelets
and heparin, and did not consider such factors as fibrinogen
conformational changes which could result upon adsorption to the different
surface.
In any case, the use of covalent heparin binding to achieve an
antithrombogenic surface may be of limited use, as exposure to blood is
expected to eventually degrade the bound heparin under the action of
heparinases.
The development of "heparinoid" materials has generally involved the
synthesis of polyelectrolytes with sulfonate and/or carboxylate
functionality. Arge, E., ACTA Med. Scand., 155, 496 (1956) and Walker et
al., Biochem. Biophys. Res. Comm., 83, 1339 (1978) have hypothesized that
the mechanism of heparin action is based on the action of the sulfate and
aminosulfate groups on the heparin molecule. Hashimoto, id., also asserted
that sulfate or sulfonate groups might simulate the action of a
heparinized surface and prevent thrombus formation. Conflicting results
were reported by Olsson et al., id., who prepared surfaces of sulfated
polysaccharrides and found them to be equally "platelet compatible" with
heparin in in vitro tests but more thrombogenic than a heparinized surface
in a canine arteriovenous shunt.
The previously mentioned study of Muranmatsu et al., id., further confuses
the issue since that study demonstrates that an increased concentration of
sulfonic acid groups in a polymer leads to a higher amount of platelet
adhesion. Jozefowicz et al., id. and Sorm et al., J. Polym. Sci., Polym.
Symp., 66, 349 (1979) contend that carboxylic functionality is also
essential for heparin-like activity. Sederel et al., J. Biomed. Mater.
Res., 15, 819 (1981) synthesized a polyelectrolyte with N-sulfate and
carboxylate groups that showed anticoagulant activity in several in vitro
trials. Ebert et al., id., found that heparin anticoagulant activity
decreased as the degree of carboxylic derivatization increased. Therefore,
it appears that the carboxylate and sulfonate functionality play a role in
anticoagulant action.
Jozefowicz and coworkers have examined the mechanisms involved in the
function of heparinoid materials. In one study, the antithrombotic
activity of crosslinked polystyrene was related to the surface density of
sulfonate groups. Kanmangne et al., Biomaterials, 6, 297 (1985). Other
studies involved the preparation and the properties of dextran
derivatives, and demonstrated that the anticoagulant activity of these
polysaccarrides was due to methylcarboxylic and sulfonated benzylamide
groups. Mauzac et al., Biomaterials, 3, 221 (1984); Mauzac et al.,
Biomaterials, 5, 301 (1984) and Fisher et al., Biomaterials, 6, 198
(1985). These studies have recently been extended by the addition of
various amino acid substituents to substituted dextran resins.
Sorm et al., id., prepared a number of synthetic polymers based on
poly(methyl methacrylate) and derivatized polymers with sulfate,
carboxylate and sulfamide groups in various proportions. The
thrombogenicity was determined with an in vitro test of the coagulation
time of plasma in the presence of thrombin. It was determined that the
highest coagulation activity was found with a copolymer containing a
relative amount of 86 percent (of total ionic content) sulfate groups and
14 percent carboxylate groups. The presence or absence of sulfamide groups
was not found to have any effect on thrombogenicity.
Helmus et al., J. Biomed. Mater. Res., 18, 165 (1984) examined the role of
surface charge of various copolymers of (L-glutamic acid co-L-leucine) and
related the surface charge to thrombus formation in implanted vascular
grafts in dogs. The initial ionic state controlled the biological
interactions. When surface concentrations of non-ionized glutamic acid
were less than 10 percent of the maximum, the amount of thrombus formed
was a linear function of the degree of ionization. When 10 percent or more
of the total surface sites comprised ionized glutamic acid residues, no
thrombus was formed, only adhesion of single platelets to the surface was
observed. The surface exposed in their canine model showed endothilization
upon long blood exposure times, but that event was correlated with the
extent of thrombus formation on the surfaces, with the surfaces showing
the most extensive thrombus formation also showing the most
endothelization.
At present, most ion-containing materials are "model ionic compounds" and
do not possess adequate mechanical integrity for biomedical applications.
Many of these polymers are hydrogels which must be bonded to a substrate
having the necessary properties for the desired application.
As noted above, many types of heparinized polyurethane block copolymers
have been tested for blood compatibility, with examples of relatively
successful [Heyman et al., J. Biomed. Mater. Res., 19, 419 (1985) and
Shibuta et al., J. Biomed. Mater. Res., 20, 971 (1986)] and unsuccessful
[Van der Lei, id. and Lelah et al., id.] attempts being reported. Studies
of "heparinoid" polyurethanes, however, are less common.
One of the first investigations of polyurethanes was by Rembaum et al.,
Biomat. Med. Dev. Art. Org., 1, 99 (1973). Polyether polyurethanes
containing positive charges in the backbone (cationomers) were synthesized
by incorporating a tertiary amine into the hard segment and reacting that
group with an alkyl halide. The particular cationic polyurethanes were not
studied, but they were reacted with sodium heparin to yield
polyurethane-heparin complexes. A chronic carotid artery-jugular vein
canine shunt was used to evaluate the thrombogenicity of this complex
together with a commercial polyurethane and silicone rubber. While little
difference was observed in the rates of platelet deposition on
non-heparinized polyurethane or silicone rubber (although the silicone
rubber was shown to cause the formation of more emboli), a retardation in
platelet deposition was observed for the polyurethane-heparin complex.
Ito et al., J. Biomed. Mater. Res., 20, 1157 (1986) examined anionic
polyurethanes with carboxylic acid functionality. The anionic polyurethane
selectively adsorbed albumin, did not cause a conformational change of
plasma proteins adsorbed and suppressed the adherence and deformation of
platelets, but did not deactivate the clotting system. Thus, the
polyurethane was considered moderately thrombogenic. A heparin-bound
derivative of this anionic polyurethane was not favorable for albumin
adsorption, caused plasma protein denaturation and induced platelet
adherence and activation, but did not activate the clotting system (as
measured by thrombin times). The question of "biocompatibility" is not yet
resolved for these materials, as one would presume that neither platelet
activation nor activation of the clotting system would be desirable.
Two separate studies by Cooper and coworkers [Lelah et al., J. Biomed.
Mater. Res., 18, 475 (1984) and Lelah et al., "Blood Compatibility of
Polyethylene and Oxidized Polyethylene in a Canine Ex Vivo Shunt:
Relationship to Surface Properties," in Polymers as Biomaterials, Shalaby
et al (eds.) Plenum Press, New York, 257--277 (1984)] demonstrated that
ionization of polyurethanes is a useful technique for improving blood
compatibility.
In the first study, two uncharged polyurethanes based on 21.5 and 38 weight
percent methylene bis(p-phenyl isocyanate) (MDI), N-methyldiethanolamine
(MDEA), and poly(tetramethylene oxide) (PTMO) having a number average
molecular weight of about 1000 were examined using the canine ex vivo
series shunt technique. Also studied were the sulfonate-containing
zwitterionic, neutralized anionic, and quarterinized cationic derivatives
of the MDEA-chain-extended base material containing 38 weight percent MDI.
The platelet deposition profiles of the polyurethane zwitterionomer and
anionomer were more thromboresistant than the uncharged polyurethane,
while the polyurethane cationomer was the most thrombogenic material of
the series. The thromboresistance of the zwitterionomer correlated with a
high concentration of the mobile side chain ionic sulfonate group at the
surface. Ionic mobility at the interface appeared to strongly influence
the blood response to these materials.
Platelet deposition profiles from a second study showed that for a
non-ionized polyurethane containing 24 weight percent MDI and the
analogous zwitterionomer, zwitterionization was found to improve the
thromboresistance of a non-ionized material. The exact mechanisms of this
action, however, were not investigated.
The base polymer utilized in the second study (in place of the
MDEA-chain-extended system) was based on MDI, PTMO having a number average
molecular weight of about 1000, and 1,4-butanediol (BD). The use of
butanediol as a chain extender provides a base material with superior
physical properties to those observed with an analogous polymer
chain-extended with MDEA. This is attributed to the superior ability of
the hard segments in the BD-chain extended system to aggregate and
crystallize. Lelah et al., Polyurethanes in Medicine, CRC Press, Boca
Raton, Fla. (1986). Butanediol is often used in commercial products, and
BD is the chain extender used in PELLETHANE polyurethanes (Lelah et al.,
id.) and in DESERET VIALON polyurethanes.
Therefore, in spite of many prior art disclosures in the area of
biocompatible materials, a need still exists for improved polymeric
materials that are more suitable for blood-contacting applications, and
which possess the desired bulk physical and surface properties.
SUMMARY OF THE INVENTION
The present invention relates to polyurethane block copolymers that include
particular polar functional groups and biocompatible devices prepared
therefrom.
The copolymers can include a mole ratio of about 1.5/0.5/1.0 to about
10/9/1 of an organic diisocyanate, a C.sub.2 -C.sub.14 alkyl or aryl or
diamine and a polyol having a number average molecular weight from about
500 to about 3000. In one preferred embodiment, the copolymer includes a
3/2/1 mole ratio of an organic diisocyanate, a C.sub.2 -C.sub.14 alkyl or
aryl diol or diamine and a polyol having a number average molecular weight
from about 500 to about 2000, more preferably about 1000.
These copolymers are further modified via a bimolecular nucleophilic
substitution reaction wherein up to about 25 percent of the urethane
hydrogen atoms, and preferably between about 10 and 15 percent of the
urethane hydrogen atoms, are replaced with a combination of lower alkyl
(C.sub.1 -C.sub.6) straight chain or branched sulfonate groups and lower
alkyl (C.sub.1 -C.sub.6) straight chain or branched carboxylate groups.
The organic diisocyanate can include 2,4-toluene diisocyanate, 2,6-toluene
diisocyanate, methylene bis(p-phenyl isocyanate), 1,5-naphthalene
diisocyanate, methylene bis(p-cyclohexyl isocyanate), 1,6-hexane
diisocyanate, isophorone diisocyanate and cyclohexyl diisocyanate.
The diol or diamine can include 1,4-butanediol, ethylene diamine,
4,4'-methylene bis(2-chloroaniline), ethylene glycol and hexanediol. The
diol and diamine can comprise a blend of two or more reactive species,
preferably having similar reactivities. In addition, a hydroxy-functional
amine such as a radical represented by the formula (HOR).sub.2 NR.sub.1
SO.sub.3 H can be used in place of or in addition to the diol or diamine.
In the above formula R and R.sub.1 can be independently selected from
lower alkyl (C.sub.1 -C.sub.6) groups. Moreover, the sulfonate group can
be replaced with a carboxylate group.
The polyol can include polyethylene oxide, polypropylene oxide,
polytetramethylene oxide, polyisobutylene, polybutadiene, polyethylene
adipate, polytetramethylene adipate, polycaprolactone and
polydimethylsiloxane. The polyol can also comprise a blend of two or more
species, preferably having similar reactivities.
It is particularly preferred to use an equimolar ratio (to within about 5
percent) of the isocyanate to the other active hydrogen atoms in the
copolymer mixture such as the hydroxyl and amine functional groups.
The present invention also relates to a method of producing the copolymers
described herein and medical devices formed with the copolymers of this
invention. Such devices are useful in applications where a biocompatible
material is needed to avoid or minimize adverse reactions upon contact
with blood or tissue.
The copolymer may comprise all of the device or only the surface which will
be in contact with the body fluids. In particular, these materials may be
used as vascular prostheses in the venous or arterial system, as heart
patches or as heart valves, as the outer encapsulant of implantable
devices such as heart pacemakers, and as catheters or the outer sheath of
catheters in contact with body fluids and the like. They may also be used
as temporary coverings for skin loss resulting from either mechanical
damage or burns, or they may be used as a covering for open wounds.
Additionally these devices may be used as channels through which body
fluids may be passed in the heart-lung and kidney machines, for example.
Indeed, the materials of these devices generally have the properties of
semipermeable membranes and may be used as such in extracorporeal devices.
Thus the present copolymers are biocompatible, and exhibit improved
physical strength and hydrophilic properties. For example, in
blood-contacting applications in which medical devices (catheters, access
shunts, implants and the like) are fabricated from these polymers,
platelet deposition decreases and platelet spreading and activation is
substantially lessened. Surface analysis of these polymers indicates that,
depending on the contacting environment, a rearrangement may take place to
minimize interfacial tension. Fibrinogen deposition on the surfaces of
these polymers is higher, which indicates a particular fibrinogen-surface
interaction during platelet contact.
In a particularly preferred embodiment, the polyurethane block copolymers
of this invention comprise the reaction product of a 3/2/1 mole ratio of
methylene bis(p-phenyl isocyanate) (MDI), 1,4-butanediol (BD) and
polytetramethylene oxide (PTMO) having a number average molecular weight
of about 1000, respectively, which reaction product is further modified in
a post-synthesis alkylation step to include from about 5 to 25 weight
percent of propyl sulfonate and propyl carboxylate groups based on the
total weight of the copolymer.
Numerous other advantages and features of the present invention will become
more readily apparent to those skilled in the art based on the following
detailed description of the invention, the accompanying examples and
drawings and the appended claims.
Claims
What is claimed is:
1. A biocompatible device having at least one surface which includes a
polyether-polyurethane copolymer based on a mole ratio of about
1.5/0.5/1.0 to about 10/9/1 of an organic diisocyanate, a C.sub.2
-C.sub.14 alkyl or aryl diol or diamine and a polyol having a number
average molecular weight from about 500 to about 3000, the copolymer being
modified wherein about 5 to about 25 percent of the urethane hydrogen
atoms are replaced with a combination of lower alkyl (C.sub.1 -C.sub.6)
sulfonate groups and lower alkyl (C.sub.1 -C.sub.6) carboxylate groups.
2. The device of claim 1 wherein said organic diisocyanate is selected from
the group consisting of 2,4-toluene diisocyanate, 2,6-toluene
diisocyanate, methylene bis(p-phenyl isocyanate), 1,5-naphthalene
diisocyanate, methylene bis(p-cyclohexyl isocyanate), 1,6-hexane
diisocyanate, isophorone diisocyanate and cyclohexyl diisocyanate.
3. The device of claim 1 wherein said diol or diamine is selected from the
group consisting of 1,4-butanediol, ethylene diamine, 4,4'-methylene
bis(2-chloroaniline), ethylene glycol and hexanediol.
4. The device of claim 1 wherein said polyol is selected from the group
consisting of polyethylene oxide, polypropylene oxide, polytetramethylene
oxide, polyisobutylene, polybutadiene, polyethylene adipate,
polytetramethylene adipte, polycaprolactone and polydimethylsiloxane.
5. A biocompatible device for biomedical applications including surgical
implantations, blood contacting procedures and the like, said device
comprising a polyurethane composition which includes a
polyether-polyurethane copolymer based on a mole ratio of about
1.5/0.5/1.0 to about 10/9/1 of (a) an organic diisocyanate, (b) a C.sub.2
-C.sub.14 alkyl or aryl diol or diamine and (c) a polyol having a number
average molecular weight from about 500 to about 3000, the copolymer being
modified wherein about 5 to about 25 percent of the urethane hydrogen
atoms are replaced with a combination of propyl sulfonate groups and
propyl carboxylate groups.
6. The device of claim 5 wherein said organic diisocyanate is selected from
the group consisting of 2,4-toluene diisocyanate, 2,6-toluene
diisocyanate, methylene bis(p-phenyl isocyanate), 1,5-naphthalene
diisocyanate, methylene bis(p-cyclohexyl isocyanate), 1,6-hexane
diisocyanate, isophorone diisocyanate and cyclohexyl diisocyanate.
7. The device of claim 5 wherein said diol or diamine is selected from the
group consisting of 1,4-butanediol, ethylene diamine, 4,4'-methylene
bis(2-chloroaniline), ethylene glycol and hexanediol.
8. The device of claim 5 wherein said polyol is selected from the group
consisting of polyethylene oxide, polypropylene oxide, polytetramethylene
oxide, polyisobutylene, polybutadiene, polyethylene adipate,
polytetramethylene adipate, polycaprolactone and polydimethylsiloxane.
9. A biocompatible device having a blood- or tissue-containing portion
comprising a poly(tetramethylene oxide) -based polyurethane composition
which comprises a polyether-polyurethane copolymer based on a 3/2/1 mole
ratio of an organic diisocyanate, a C.sub.2 -C.sub.14 alkyl or aryl diol
or diamine and a polytetramethylene oxide having a number average
molecular weight of about 1000, the copolymer being modified wherein about
5 to about 25 percent of the urethane hydrogen atoms are replaced with a
combination of propyl sulfonate groups and propyl carboxylate groups.
10. The device of claim 9 wherein said organic diisocyanate is selected
from the group consisting of 2,4-toluene diisocyanate, 2,6-toluene
diisocyanate, methylene bis(p-phenyl isocyanate), 1,5-naphthalene
diisocyanate, methylene bis(p-cyclohexyl isocyanate), 1,6-hexane
diisocyanate, isophorone diisocyanate and cyclohexyl diisocyanate.
11. The device of claim 9 wherein said diol or diamine is selected from the
group consisting of 1,4-butanediol, ethylene diamine, 4,4'-methylene
bis(2-chloroaniline), ethylene glycol and hexanediol.
12. A device for biomedical use comprising a poly(tetramethylene
oxide)-based polyurethane composition which comprises a
polyether-polyurethane copolymer based on a 3/2/1 mole ratio of methylene
bis(p-phenyl isocyanate), 1,4-butanediol and polytetramethylene oxide
having a number average molecular weight of about 1000, the copolymer
being modified wherein about 5 to about 25 percent of the urethane
hydrogen atoms are replaced with a combination of propyl sulfonate groups
and propyl carboxylate groups.
Description
DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates infrared absorption spectra for a polyurethane and a
polyurethane ionomer having about twenty percent of the urethane hydrogen
atoms replaced with propyl sulfonate groups.
FIG. 2 illustrates differential scanning calorimetry (DSC) curves for
sulfonated polyurethanes.
FIG. 3 illustrates the results of dynamic mechanical analysis for a
non-ionized polyurethane and for polyurethanes with low and high levels of
ionization.
FIG. 4 illustrates the stress-strain curves for a non-ionized polyurethane
and for certain sulfonated polyurethane ionomers.
FIG. 5 illustrates the stress-strain curves for a non-ionized polyurethane
and for ionomers having both sulfonate and carboxylate functionality.
FIG. 6 illustrates the C.sub.1S high resolution ESCA spectra for a
non-ionized polyurethane and for ionomers having sulfonate functionality.
FIGS. 7-10 illustrate platelet and fibrinogen deposition profiles for a
polyurethane and for polyurethane ionomers having sulfonate or sulfonate
and carboxylate functionality.
FIG. 11 illustrates platelet adherence to a non-ionized polyurethane
surface as a function of blood exposure time.
FIG. 12 illustrates platelet adherence to a polyurethane surface having
moderate sulfonate functionality as a function of blood exposure time.
FIG. 13 illustrates platelet adherence to a polyurethane surface having
high sulfonate functionality as a function of blood exposure time.
FIG. 14 illustrates platelet adherence to a polyurethane surface having a
moderately high sulfonate functionality after exposure to blood for 30
minutes.
DETAILED DESCRIPTION OF THE INVENTION
For purposes of illustrating the present invention and the practice
thereof, the method of preparing the present polyurethane block copolymers
and the preparation of certain chemical intermediates is described with
reference to particular examples of copolymers and testing procedures for
determining bulk and surface characteristics, and the biocompatibility of
the copolymers. It will be understood, however, that the copolymers of
this invention are not limited only to those materials specifically
described herein.
In accordance with the present invention, modifications to the polymer
chain are performed, and bulk characterization techniques are utilized for
the analysis of properties such as microphase separation. Bulk properties
are related to surface properties, and the resulting polyurethane ionomers
are evaluated for blood compatibility through a canine ex vivo
blood-contacting experimental procedure. Although bulk modifications are
performed, it should be recognized that the present polymer compositions
can readily be used for coatings, or can be adapted for use as surface
modifying agents.
I. MATERIALS AND METHODS
A polyether-polyurethane (PEU) based on methylene bis(p-phenyl isocyanate)
(MDI), 1,4-butanediol (BD) and a polytetramethylene oxide (PTMO) having a
number average molecular weight of about 1000 is first synthesized in a
3/2/1 mole ratio. The chemical structures of the starting materials shown
below:
______________________________________
methylene bis(p-phenyl isocyanate)
(MDI)
OCN-C.sub.6 H.sub.4 -CH.sub.2 -C.sub.6 H.sub.4 -NCO
1,4-butanediol (BD)
HO-CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 -OH
polytetramethylene oxide, 1000 MW
(PTMO)
HO-(CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 O).sub.n H
______________________________________
A grafting reaction procedure is performed employing a bimolecular
nucleophilic displacement reaction of the urethane hydrogen atoms. The
urethane nitrogens are first reduced by reaction with sodium hydride in a
solvent such as N,N-dimethylacetamide (DMA) which results in the
production of hydrogen gas. This reaction is followed by reaction with
1,3-propane sultone which reacts with the nitrogen anion to produce a
derivatized urethane linkage. The extent of sulfonate substitution is
systematically varied from about 5 to about 20 percent replacement of the
urethane hydrogen atoms.
The sodium salt of 4-iodobutanoic acid (Aldrich Chemical Co., Milwaukee,
Wis.) can be used instead of propane sultone for polymers having twenty
percent of the urethane hydrogen atoms replaced. The synthetic procedure
in this instance is essentially the same, except that a mixed solvent of
DMA and dimethyl sulfoxide (DMSO) (in a 3:1 ratio by volume) is used
because of the limited solubility of iodopropionic acid in DMA.
A. Sample Preparation
After synthesis, the modified copolymers are extracted for about 48 hours
with toluene in a Soxhlet extractor to remove contaminants, oligomeric
materials and any residual propane sultone that may be present. After
briefly drying under vacuum to remove residual toluene, the resulting
copolymers are dissolved in DMA and then cast into Teflon pans for bulk
property testing or are coated into the inner lumen of chromic
acidoxidized polyethylene tubing for surface property and blood
compatibility evaluation. In both casting procedures, cast films are first
dried under a nitrogen stream (in the case of tubing) or in a 70 degree C
forced-air oven (for bulk sheets) for at least 48 hours to remove most of
the DMA. The final drying stage involves drying the coated tube or sheet
under vacuum at 60 degrees C for at least 48 hours to remove any residual
DMA.
Typically, polyurethane elastomers comprise rigid and flexible alternating
segments. The hard (rigid) segment consists of a diisocyanate that has
been chain extended with a low molecular weight diol or diamine. The soft
(flexible) segment is a long chain macroglycol with a number average
molecular weight between about 500 and 5000.
Preferred isocyanates for use in the practice of the present invention
include 2,4-toluene diisocyanate, 2,6-toluene diisocyanante, methylene bis
(p-phenyl isocyanate), 1,5-naphthalene diisocyanate, methylene
bis(p-cyclohexyl isocyanate), 1,6-hexane diisocyanate, isophorone
diisocyanante and cyclohexyl diisocyanante.
Preferred chain extenders include 1,4-butanediol, ethylene diamine,
4,4-methylene bis(2-chloroaniline), ethylene glycol and hexanediol.
Preferred polyols include polyethylene oxide, polypropylene oxide,
polytetramethylene oxide, polyisobutylene, polybutadiene, polyethylene
adipate, polytetramethylene adipate, polycaprolactone and
polydimethylsiloxane.
B. Sample Nomenclature
A list of the particular copolymers prepared and the nomenclature used
herein is shown in Table I.
TABLE I
______________________________________
SAMPLE DESIGNATIONS
Percent of Urethane Hydrogens Replaced
Total Percent Replaced
Percent Replaced
Percent Using Propane
Using Iodo-
Polymer Replaced Sultone Butyric Acid Salt
______________________________________
PEU 0 0 0
PEU-SO3-0.05
5 5 0
PEU-SO3-0.10
10 10 0
PEU-SO3-0.15
15 15 0
PEU-SO3-0.20
20 20 0
SO3-0.15 20 15 5
COO-0.05
SO3-0.10 20 10 10
COO-0.10
______________________________________
As indicated in TABLE I, the control non-ionized polyurethane is referred
to as PEU. Sulfonate incorporation is denoted by SO3 to distinguish those
materials from materials prepared by grafting long alkyl chains to the
base PEU polymer. The fraction of urethane hydrogens substituted is
indicated by the final portion of the sample designation. Thus,
PEU-SO3-0.20 has a twenty percent displacement of urethane hydrogen atoms
with propyl sulfonate groups. Polyurethanes having both sulfonate and
carboxylate functionality are not identified herein with the PEU
designation; but are identified, for example, with the designation
SO3-0.15 COO-0.05, which indicates fifteen percent displacement of
urethane hydrogen atoms with propyl sulfonate groups and five percent
displacement of urethane hydrogen atoms with propyl carboxylate groups.
See TABLE II.
C. Bulk Property Characterization
Differential scanning calorimetry (DSC) thermograms are recorded from -150
degrees C. to 230 degrees C. using a Perkin-Elmer DSC-2 equipped with a
data-processing unit that subtracts background readings and normalizes
sample thermograms for sample weight. The heating rate is 20 degrees
C./min for the initial heating up to 200 degrees C. Samples are
quench-cooled to -130 degrees C. at 320 degrees C./min and then reheated
at a rate of 20 degrees C./min.
Transmission infrared spectroscopy is performed with a Nicolet 7199 FTIR
operating at a resolution of 2 reciprocal centimeters (cm.sup.-1). Dynamic
mechanical analysis is accomplished with a microprocessor-controlled
Rheovibron DDV-II. Samples are cooled to -150 degrees C., and data are
taken at a test frequency of 110 Hz and a temperature rise rate of 2
degrees C/min until sample failure. Room temperature uniaxial
stress-strain data are taken on an Instron table model tensile testing
device at a crosshead speed of 0.5 inch/min (57 percent/min.). Samples are
prepared using an ASTM 1708 standard die.
D. Surface Property Determination
Surface properties are determined directly on a coated polyethylene surface
prior to exposure to blood. Random sections of a coated polyurethane tube
are selected for the various methods of analysis. The contact angle data
from the numerous sections tested indicate that the coatings are
consistent and uniform in all sections of tubing for each material tested.
ESCA data are collected using a Surface Science Laboratories SSX-100 ESCA
spectrometer using an AlK.sub.alpha x-ray source. The characteristics of
this instrument have been described by Yoon et al., Macromolecules, 19,
1968 (1986), and the same instrument operating under the same conditions
has been used to characterize the surface structure of the present
polyurethane copolymers. The circular spot size irradiated with
monochromatic x-rays is 600 micrometers in diameter. Surface charging
which occurs as a result of the non-conductive surfaces is neutralized
with an electron flood gun. High resolution C1 s spectra are obtained
using a 25 eV pass energy, and spectra for the determination of elemental
percentages are obtained for all elements present at a 100 eV pass energy.
A 30 degree solid-angle electron collection aperture is used in the
electron lens system, and all spectra are collected at a single take-off
angle of 55 degrees. All ESCA data are processed using the software
provided with the instrument. The C1 s core level spectra of the polymers
can be resolved with reference to known binding energy data for
nitrogen-substituted polymers or model compounds using the assumption of
Gaussian peak shapes.
Attenuated total reflectance (ATR) infrared spectroscopy is performed using
a Nicolet 7199 FTIR, coupled with a Barnes 300 ATR accessory and 45 degree
germanium crystal coated tubings are sliced and pressed against the
crystal. Spectra are collected at a resolution of 2 cm.sup.-1.
Underwater contact angle measurements are made using the captive bubble
technique of Hamilton, J. Colloid Interface Sci., 40, 219 (1972), modified
for use on curved inner tubing surfaces. At least twelve separate
measurements are performed on at least five different, randomly selected
tubing sections of each material. Each surface is allowed to equilibrate
under double-distilled water overnight. Surface-air-water and
surface-octane-water static bubble contact angles are measured. When
possible, polar and dispersive components of the surface energy and the
surface-water interfacial energy are calculated using harmonic mean and
geometric mean approximation methods. Advancing and receding contact
angles of water on polymer-coated tubings are measured using methods well
known to those skilled in the art. All measured contact angles are
reported as the angles through the water phase.
E. Blood Compatibility Evaluation
A study using a canine ex vivo series shunt is used to evaluate the blood
compatibility of these polyurethane block copolymers. Blood exposure times
range from 1 to 60 minutes. Each material is examined in three separate
random segments in each shunt. A control surface of INTRAMEDIC
polyethylene can be examined in each shunt, if NIH Standard Reference
Polyethylene is not available in the necessary inner diameter.
The animal studies were performed as described in Lelah et al., J. Biomed.
Mater. Res., 18, 475 (1984) which is incorporated herein by reference.
Initial flow rates are carefully controlled using a clamp (downstream from
the test sections) to average levels of 300 m/min (.+-.5 percent) which
corresponds to an average wall shear rate of about 1600 sec.sup.-1.
Samples prepared for scanning electron microscopy are viewed using a
JEOL-JSM 35C at a 12 kV accelerating voltage.
II. RESULTS AND DISCUSSION
A. Infrared Spectroscopy
FIG. 1 shows the infrared survey spectra for PEU and an ionomer designated
PEU-SO3-0.20. The absorption band of the --NH bond at 3340 cm.sup.-1 was
clearly reduced in intensity following substitution.
The other important difference in the spectra of FIG. 1 is in the carbonyl
band between 1650 and 1750 cm.sup.-1. In the non-ionized PEU polymer, the
carbonyl absorption is found at 1730 cm.sup.-1 this represents "free"
carbonyl groups that do not hydrogen bond with urethane NH groups; and to
a larger extent at 1700 cm.sup.-1, hydrogen-bonded carbonyl groups. While
the urethane carbonyl groups were primarily hydrogen-bonded in the PEU
base material, the relative fraction of free carbonyl groups was much
greater in PEU-SO3-0.20 than in PEU. Similar results observed in
sulfonated polyurethane systems can be attributed to the possibility that
the urethane groups bind to the stronger proton-accepting sulfonyl groups
instead of to the carbonyl group. Another explanation for the increase in
free carbonyl upon ionization is that there is a disruption of ordered
hard segment packing arrangements upon ionization.
The first column of Table II includes numerical comparisons of the
"nonbonded" to "bonded" urethane carbonyl ratio in the bulk, and it can be
seen that the proportion of nonbonded carbonyl groups goes through a
maximum as the level of ionization is increased. The relative similarity
between the spectra of polymers PEU-SO3-0.20, SO3-0.15 COO--0.05, and
SO3-0.10 COO-0.10 indicates that the hard segment ordering is primarily a
function of the percentage of urethane hydrogen substitution.
TABLE II
______________________________________
INFRARED SPECTROSCOPIC ANALYSIS
OF POLYURETHANE ANIONOMERS
"Nonbonded" to
"Bonded" Urethane
"Hard" to "Soft"
Carbonyl Absorbance
Segment
Ratio.sup.a Absorbance Ratio.sup.b
Polymer Bulk ATR Bulk ATR
______________________________________
PEU 0.57 0.55 0.49 0.36
PEU-SO3-0.05
0.83 0.72 0.50 0.39
PEU-SO3-0.10
1.09 0.75 0.48 0.35
PEU-SO3-0.15
1.14 0.78 0.48 0.38
PEU-SO3-0.20
1.05 0.98 0.48 0.39
SO3-0.15 COO-0.05
1.07 1.00 0.50 0.40
SO3-0.10 COO-0.10
0.99 0.98 0.48 0.40
______________________________________
.sup.a A(1702 cm.sup.-1)/A(1732 cm.sup.-1)
.sup.b A(1597 cm.sup.-1)/A(1111 cm.sup.-1)
The "hard-to-soft" segment absorbance ratio, or the ratio of absorbance at
1597 cm.sup.-1 (which is characteristic of the benzene ring in the hard
segment) and at 1111 cm.sup.-1 (which is characteristic of the polyether
in the soft segment) shows little variation in the bulk infrared spectra.
This result is expected because the chemical changes in the bulk to these
polymers are not significant.
B. Thermal Analysis
DSC curves are shown in FIG. 2 for the sulfonated polyurethanes, and the
thermal analysis data are summarized in Table III. For each copolymer,
FIG. 5 shows the DSC curves for the initial heating at 20 C/min of the
as-cast sample (solid lines) and after reheating of the sample at a rate
of 20 degrees C/min (dotted lines) and quench-cooling at -320 degrees
C/min. The data are consistent with prior art thermal studies of similar
polyurethane anionomers.
Initially, there is no significant change in the glass transition
temperature (Tg) of the soft segment, but increasing the degree of
ionization to the levels of PEU-SO3-0.10 and PEU-SO3-0.15 produces
materials with a high soft segment Tg which indicates a decrease in the
degree of phase separation with ionization. As noted in the foregoing
discussion of the infrared spectroscopic data, this increase in Tg is
probably the result of a disruption of hard segment ordering and an
increased solubilization of hard segments in the soft segment phase.
Further ionization for copolymer PEU-SO3-0.20 causes the soft segment Tg to
become about equal to that of the unmodified PEU. This indicates an
increase in phase separation which is consistent with the infrared
observations where a decrease in nonbonded urethane hydrogen was observed
at the highest ionization level. The increase in the hard/soft segment
polarity difference upon ionization is the probable driving force for
increased phase separation, and this polarity difference appears to
overcome the unfavorable hard segment packing arrangements.
An endotherm at high temperature was observed for PEU, as shown in FIG. 2.
In the absence of high-temperature annealing, endotherms occurring at
temperatures over 100 degrees C are associated with long-range order in
the hard segment. The disappearance of high-temperature endotherms upon
ionization confirm that hard segment ordering is less in ionized
polyurethanes than in PEU.
When PEU is quenched from a high temperature, a relatively phase-mixed
state is "frozen" in, resulting in a relatively high soft segment glass
transition temperature when the material is reheated. As shown in FIG. 2,
the magnitude of this Tg shift upon quenching is greatest for the
relatively well-phase-separated PEU material and decreases upon
ionization. The phase separated PEU-SO3-0.20, however, does not exhibit
this Tg shift.
Table III shows that the polyurethane anionomers with both sulfonate and
carboxylate groups are quite similar to PEU-SO3-0.20, and all DSC curves
of these carboxylated systems are nearly indistinguishable from the
completely sulfonated PEU-SO3-0.20.
TABLE III
______________________________________
Thermal Analysis Data for Polyurethane Anionomers
Glass Transition Temperature, C.
for heating after
for initial heating:
quench:
Polymer Midpoint Onset Midpoint
Onset
______________________________________
PEU -44 -60 -30 -47
PEU-SO3-0.05
-45 -62 -24 -53
PEU-SO3-0.10
-35 -62 -28 -53
PEU-SO3-0.15
-36 -62 -36 -61
PEU-SO3-0.20
-46 -70 -44 -70
SO3-0.15 COO-0.05
-47 -71 -44 -70
SO3-0.10 COO-0.10
-45 -71 -44 -70
______________________________________
This similarity indicates a likeness in bulk morphologies between these
materials, and indicates that the polymer physical properties are more a
function of the percentage of urethane hydrogen displacement than of the
type of ionic functionality that is present.
C. Dynamic Mechanical Analysis
The results of dynamic mechanical analysis for the non-ionized PEU, and for
low and high levels of ionization, are presented in FIG. 3. These results
are consistent with the DSC data. A significantly higher plateau modulus
is observed in PEU-SO3-0.20, which can be attributed to the regaining of a
high degree of phase separation along with an enhanced domain cohesion due
to the high ionic content. Dynamic mechanical behavior for SO3-0.15
COO-0.05 and SO3-0.10 COO-0.10 is similar to that of PEU-SO3-0.20, which
is expected considering the similarity of results of the other bulk
characterization methods.
A high temperature transition, not detected by DSC and believed to be a
hard segment glass transition, has been detected for these polymer systems
in prior art disclosures, and may be indicated in FIG. 6 for PEU-SO3-0.20.
Heating past this transition results in a dimensional stability even lower
than that observed for the non-ionized PEU. This drop in the storage
modulus at high temperature reduces the high-temperature utility of these
ionized materials.
D. Tensile Properties
Stress-strain data are summarized in Table IV, and stress-strain curves are
shown in FIGS. 4 and 5. The tensile behavior of these materials is
consistent with prior art disclosures for polyurethane ionomers. Low
levels of ionization render greater ultimate properties but tend to
decrease the modulus. This observation is consistent with the dynamic
mechanical data in which little change in the E' was seen at low
ionization levels. A sudden jump in the modulus was observed as the
highest level of ionization was reached.
All of the materials containing a total of twenty percent substitution of
the urethane hydrogen atoms possessed a significantly higher Young's
modulus than the other polyurethanes studied. However, as shown in Table
IV and in FIG. 5, replacing some of the sulfonate groups with carboxylate
functionality substantially decreased both percentage elongation and
stress at failure.
TABLE IV
__________________________________________________________________________
Physical Properties for Polyurethane Anionomers
Percent (of original weight) water
Percent
absorbed after 48 hrs. at room
temperature:
Young's Modulus
Ultimate Stress
Elongation
after exposure to air
after immersion
Polymer PSI MPa PSI MPa at Failure
(50 percent humidity)
in water
__________________________________________________________________________
PEU 4400 30 3600
25 620 0.28 2.2
PEU-SO3-0.05
3900 27 3400
23 500 0.28 4.3
PEU-SO3-0.10
4200 29 4100
28 550 0.41 31.0
PEU-SO3-0.15
4500 31 5500
38 540 0.50 150
PEU-SO3-0.20
21500
148 8300
57 480 0.56 >1000
SO3-0.15 COO-0.05
18000
124 5710
39 450 ND ND
SO3-0.10 COO-0.10
15000
103 3400
23 420 ND ND
__________________________________________________________________________
ND = Not Determined
This observation and the decrease in Young's modulus with an increase in
the proportion of carboxylate substitution suggest that the hard segment
domain cohesion decreases with the level of carboxylate incorporation into
the copolymer. The carboxylate substitution still affected the polymer
properties, however, because the modulus and stress at failure were higher
for SO3-0.10 COO-0.10 than for the PEU-SO3-0.10. Similarly, SO3-0.15
COO-0.05 had a higher modulus and stress at failure than PEU-SO3-0.15.
The ionized materials were found to be somewhat water-sensitive to the
point that the tensile properties were significantly affected by exposure
to the atmosphere. Water absorption results are shown in TABLE IV for
polymer samples stamped out of an ASTM 1708 die and either equilibrated
for 48 hours in air at room temperature and 50 percent relative humidity
or placed underwater for 48 hours. The largest drop in properties was
observed for PEU-SO3-0.2. A sheet of this material that was exposed to the
atmosphere as described above showed a drop in Young's modulus to 80 MPa,
a drop in ultimate tensile strength to 31 MPa, and decrease in elongation
at break to nearly 300 percent, in spite of having measured weight gain
well below 1 percent. Hwang et al., J. Macromol. Sci. Phys., B23, 153-174
(1984) noted that similar polymers with ionic contents corresponding to
urethante hydrogen replacement levels of over 22 percent absorbed water
from the atmosphere and were rendered insoluble in DMA. As indicated in
Table IV, when PEU-SO3-0.2 was soaked in water overnight, a polymer-water
hydrogel formed weighing over ten times more than the base polymer. Water
uptake under these conditions was a strong function of ionic content,
ranging from 2 percent for the base polymer PEU to 150 percent for
PEU-SO3-0.15. While the problem of hydration may have to be accounted for
in the use of these materials for applications requiring equilibration
with the atmosphere, the use of these polymers as coatings onto substrata
for blood-contacting applications is not precluded.
E. Surface Properties: Attenuated Total
Reflectance Infrared (ATR) Spectroscopy
Because of the relatively deep penetration of this technique (1000-10,000
A), good agreement of trends in transmission and total reflectance
infrared spectroscopy would be expected. While numerical results for
transmission infrared spectroscopy and bulk infrared spectroscopy cannot
be directly compared, the trends in the transmission and reflectance
spectra although not identical, provide some information about the surface
chemical composition relative to that of the bulk.
Table II shows that as the degree of sulfonation increased, the relative
ratio of nonbonded-to-bonded urethane carbonyl groups passes through a
maximum in the bulk. The ATR spectra for the moderately ionized materials
(PEU-SO3-0.05, PEU-SO3-0.10 and PEU-SO3-0.15) were quite similar.
Moreover, the ratio of nonbonded-to-bonded urethane carbonyl groups did
not pass through a maximum with increasing ionic content, as was observed
in the bulk polymers of this series. One explanation of this occurrence is
that in materials with low ionization levels, there is a relative absence
of sulfonate groups near the surface in the air-equilibrated environment
of the ATR/FTIR technique. In the absence of sulfonate groups, the
urethane carbonyl have to hydrogen-bond to urethane hydrogen atoms in the
surface region. The net result is a larger-than-expected proportion of
hydrogen-bonded urethane carbonyl groups near the surface.
All of these polymers have approximately the same hard to soft segment
ratio in the bulk. As seen in Table II, there is very little change in the
hard-to-soft segment absorbance ratio for these materials either in the
bulk or within the penetration depth of the ATR technique.
F. ESCA Analysis of the Surface Region
The results of the ESCA analysis of the anionomers of the present invention
are shown in Table V, and a comparison of C.sub.1S high resolution spectra
of several of the materials is shown in FIG. 6. The C.sub.1S spectra
consist of several well-resolved peaks. The main peak, referenced to 285.0
eV, is due to unsubstituted aliphatic and aromatic carbon atoms. The peak
that is shifted approximately 1.5 eV towards the higher binding energy
side of the main peak corresponds to carbon atoms that are single-bonded
to oxygen atoms. The small peak shifted approximately 5 eV towards the
higher binding energy side of the main peak corresponds to carbon atoms
that are double-bonded to oxygen atoms in the urethane linkage.
The 286.5 eV "ether" carbon is present in the soft segment and in the
urethane linkage. However, the ratio of ether carbon to aliphatic/aromatic
carbon in the soft segment is about 0.5, while this ratio for the pure
hard segment is about 0.105. Thus, changes in the relative size of the
286.5 eV peak provide an indication of surface hard/soft segment
composition. While nitrogen and carbonyl carbons (290 eV) are
characteristic of the hard segment, it is known that short hard segment
repeat units are mixed into the soft segment phase. The analysis of these
materials is aided by the fact that with the exception of sulfur, the bulk
elemental composition is virtually identical (constant to within 2
percent) at the level of accuracy of the ESCA technique.
The data presented in Table V show that there are no major differences in
the ESCA spectra of these materials. Atomic percentages of carbon,
nitrogen, and oxygen are all very similar. Sodium incorporation is not
easily detected by the instrument. The level of sulfur, indicative of the
ionic group incorporation, is on the same order as the value of 0.7
percent predicted by the stoichiometry for PEU-SO3-0.20. As in the case
with sodium, the resolution of the instrument probably is not sufficient
to interpret any trends in sulfur incorporation. However, the observed
levels of nitrogen and carbonyl carbon were considerably below the value
of 4.3 percent for each that is predicted by the stoichiometry.
FIG. 6 shows the C.sub.1S high resolution ESCA spectra for polymers PEU,
PEU-SO3-0.10 and PEU-SO3-0.20. The curves for PEU and PEU-SO3-0.20 were
virtually superimposable, which indicates very similar surface
morphologies in vacuo. However, somewhat less ethereal carbon is indicated
on PEU-SO3-0.10 than on the other materials. A surface depletion of
ethereal carbon is indicated in Table V for the intermediate levels of ion
incorporation.
TABLE V
__________________________________________________________________________
ESCA Analysis of Polyurethane Anionomers
ESCA Atomic Percentage
Polymer C.sub.total
C.sub.285eV
C.sub.285.5eV
C.sub.290e-V
N O S Si
__________________________________________________________________________
PEU 78 46 31 1.0 2.3
19 0 0.4
PEU-SO3-0.05
81 49 31 1.1 2.2
14 0.1
0.5
PEU-SO3-0.10
81 57 23 1.2 2.5
16 0.4
0.2
PEU-SO3-0.15
80 56 22 1.3 2.4
17 0.6
0.3
PEU-SO3-0.20
82 49 31 1.5 2.5
15 0.6
0.4
SO3-0.15 COO-0.05
81 49 31 1.1 2.3
15 0.5
1.1
SO3-0.10 COO-0.10
83 54 28 1.2 2.2
14 0.2
0.8
__________________________________________________________________________
It can be seen in FIG. 6 that the resolution of the peaks was not identical
for PEU-SO3-0.10 as for the other polymers, and the process of fitting
Gaussian peaks and resolving the spectra of PEU-SO3-0.10 and PEU-SO3-0.15
was made somewhat more difficult. Still, difficulties with curve
resolution do not fully explain differences from the base material of 25
percent that were observed. The bulk characterization indicated that
copolymers PEU-SO3-0.10 and PEU-SO3-0.15 were more poorly phase-separated
than the base material and had a greater degree of hard segment in the
soft segment phase. As hard segments become mixed into the soft segment
phase, the proportion of aliphatic/aromatic carbon will increase, and that
trend was observed with PEU-SO3-0.10 and PEU-SO3-0.15. Changes in the
level of surface nitrogen also increase slightly with ionization, but the
signals are small, and that observation must be carefully interpreted.
The level of silicon on the surface was not reproducible, even between
replicate samples of the same copolymer. This suggests a small, patchy
amount of poly(dimethylsiloxane) contamination. As indicated in
wettability studies, however, a hydrophobic surface that would be
characteristic of a silicone overlayer is not indicated for any of these
materials.
In summary, the ESCA data indicate that there is surface soft segment
enrichment for all of these polymers. Although some change in the C.sub.1S
spectra may be observed with low-to-moderate levels of ionization, the
similarity between the ESCA spectra of PEU and PEU-SO3-0.20 is striking
and indicated that the in vacuo surface chemistry of these materials is
similar.
G. Contact Angle Analysis
Contact angle data are shown in Table VI. As the surface polarity of a
material increases, the contact angle as measured through the water phase
should decrease. The contact angle data indicate that as the level of
sulfonation increases, the polyurethanes become much more hydrophilic. In
fact, air bubbles do not adhere reproducibly to the surface of
PEU-SO3-0.20 when the sample is under water. This behavior is unexpected
and unlike what has been observed for other polyurethane systems,
including some polyurethane ionomers, examined using the same underwater
contact angle technique. The nonadherence of air bubbles to highly polar
surfaces is, in fact, a limitation of the underwater contact angle
technique when it is used to determine surface energetics, and it
indicates that the polar component of the solid surface energy is above 53
dynes/cm.
TABLE VI
______________________________________
Contact Angle/Wettability Data for Polyurethane Ionomers
Underwater Contact
Angle Measured
Through the Surface- In-Air
Water Phase:
Water Contact
Surface-
Surface- Interfacial
Angle
water-air
water-air
Energy, (degrees)
Polyemr (degrees)
(degrees)
(dyn/cm)
adv. rec.
______________________________________
PEU 62 .+-. 7
85 .+-. 8
15 78 63
PEU-SO3-0.05
37 .+-. 3
58 .+-. 5
7 ND ND
PEU-SO3-0.10
33 .+-. 4
46 .+-. 6
<5 60 35
PEU-SO3-0.15
26 .+-. 4
30 .+-. 4
<5 ND ND
PEU-SO3-0.20
<10 34 .+-. 4
<5 37 37
SO3-0.15 <10 30 .+-. 3
<5 ND ND
COO-0.05
SO3-0.10 17 .+-. 3
39 .+-. 8
<5 ND ND
COO-0.10
______________________________________
ND = Not Determined
The use of harmonic or geometric mean equations with the underwater captive
bubble technique to obtain surface energy values is controversial, and the
significance of the actual surface energy values that may be calculated
for these polymers may be questionable. However, it is apparent that even
the base material has polar character, and the extent of this polarity
increases substantially upon ionization. The sharp differences in surface
wettability between PEU and PEU-SO3-0.20 are in sharp contrast with the
relatively small differences observed between these materials using the in
vacuo ESCA technique. The differences between the results of the two
techniques suggest that the polyurethane surfaces are mobile and capable
of rearranging to minimize their interfacial tension with the environment.
Among the anionomers containing a twenty percent replacement of the
urethane hydrogen, it is seen in Table VI that the wettability, although
high when compared to the other polymers, decreases as the proportion of
carboxylate derivatization is increased. This observation indicates that
the highly acidic character of the sulfonate group compared to the
carboxylate group contributes to the wettability and perhaps the ability
of the functional group to orient toward a water-contacting interface.
The water-in-air advancing and receding contact angles measured inside the
coated tubings indicate similar trends and variations. The wettability of
the polyurethane is observed to increase strongly upon ionization. The
apparent contact angle hysteresis initially increased with ionization and
then decreased to a very small level. Since many different phenomena
contribute to contact angle hysteresis, it is difficult to separate the
different factors which will change the observed hysteresis. For example,
scanning electron microscopic examination of the dry surfaces did not
reveal visible roughness, but surface molecular mobility, which can affect
contact angle hysteresis, may still be present in the hydrated surfaces.
These results do suggest, however, that the presence of ionic groups has a
strong effect on both the advancing and receding contact angles. The
advancing angle is characteristic of the nonpolar component of a surface,
while the receding angle, in the absence of factors such as surface
roughness, is especially sensitive to the polar component. Thus, it
appears that the dispersive component of the surface disappears upon
ionization.
H. Blood Compatibility
A surface is considered to be "thrombogenic" if relatively large numbers of
platelets and/or fibrinogen molecules adhere to it. FIGS. 7-10 show
platelet and fibrinogen deposition profiles which were determined over the
initial hour of blood contact for the polymers of the present invention.
Two sets of animal experiments, each set consisting of three different
dogs, are performed.
Very different platelet and fibrinogen responses, spanning several orders
of magnitude, are observed with these materials. Because of these
unexpected results, and because platelet and fibrinogen deposition levels,
by necessity, have a lower bound of zero, it is not surprising to observe
that symmetric distributions of platelet or fibrinogen deposition around
an arithmetic mean for a given material and time point are almost never
observed. Thus, for the purposes of data analysis, a logarithmic transform
was employed. The mean+SD was then determined, and the data were
re-transformed for plotting. Animal-to-animal variation was a significant
factor in the first surgery set and may also be expected in a clinical
blood-contacting situation. It is very important to note, however, that
each animal showed the same trends in thrombus deposition. Thus, it was
decided to simplify the data analysis and reporting of data by lumping the
animals together from each surgery set in an attempt to see if material
variations play a role in the blood-material interactions.
The role of the thrombotic potential of the animal in determining the
actual extent of blood-material interactions has been disclosed in the
prior art. The dogs used herein were initially prescreened for platelet
aggregability to ADP and epinephrine, platelet counts of 150,000-400,000
reciprocal microliters, a fibrinogen levels of 100-300 mg/dl and
hematocrit levels of 35-50.
In terms of platelet aggregability, in particular, all animals were well
within the acceptable range. During the course of the study, platelet and
plasma fibrinogen levels and packed cell volumes remained essentially
unchanged. The euglobulin lysis times (ELT), activated thromboplastin time
(PTT) and prothrombin times remained unchanged during the course of the
experiments, although in one surgery the ELT was somewhat lower than
normal. In summary, however, no monitored hematological parameters were
found to correlate with the enhanced platelet response of one animal or
the low fibrinogen response of the other.
The first set of animal experiments studied the effect of sulfonate
incorporation into the polyurethane block copolymer, and the results of
the ex vivo animal studies are shown in FIGS. 7 and 8. Table VII contains
the results of two-sided t-tests which were performed for selected pairs
of surfaces at each time point of blood exposure. At low levels of
ionization (PEU-SO3-0.05), there was no significant effect of ion
incorporation on platelet deposition, but some significant decreases in
platelet deposition were observed at several time points on PEU-SO3-0.10.
Platelet deposition decreased as ionic content was further increased. The
mean platelet deposition levels observed for PEU-SO3-0.15 and
PEU-SO3-0.20, at under 10 platelets/1000 m.sup.2 for 30 minutes of blood
exposure, are lower than previously seen for any other tested material in
the same ex vivo blood-contacting experiment.
TABLE VII
__________________________________________________________________________
Statistical Analysis of Ex Vivo Animal Surgery Results
Materials
Platelets
Being or Time point of Comparison (min.)
Compared Fibrinogen
5 10 15 20 25 30 45 60
__________________________________________________________________________
PEU & platelet
+++ - - + + + - -
PEU-SO3-0.10
(SET #1) fibrinogen
++ - - ++ - - - -
PEU & platelet
+++ +++ ++ ++ ++ ++ - -
SO3-.1 COO-.1 &
platelet
- +++ +++ +++ +++ ++ - -
SO3-.15 COO-.05
fibrinogen
+++ +++ +++ +++ +++ +++ +++ +++
__________________________________________________________________________
Key for Table VII:
+++ Null hypothesis (that mean deposition levels for the materials being
compared are identical) may be rejected with 99.9 percent level of
confidence.
++ Null hypothesis may be rejected at 99 percent confidence level.
+ Null hypothesis may be rejected at 90 percent confidence level.
- Null hypothesis may not be rejected at 90 percent confidence level or
higher.
FIG. 8 shows the fibrinogen deposition profiles for the ionized
polyurethanes. The fibrinogen deposition profile for PEU-SO3-0.05 (not
shown) is comparable to that of PEU. This indicates no significant effects
of low ionization levels. This observation is interesting in light of the
significantly higher wettability of PEU-SO3-0.05 as compared to PEU.
Increasing the sulfonation level to that of PEU-SO3-0.10 resulted in
decreased mean fibrinogen deposition levels at each blood contact time.
Table VII indicates, however, that when each time point is individually
considered, the difference between the PEU-SO3-0.10 ionomer and PEU was
only significant at two time points. The lack of significance is
attributed to the inter-animal variation and the global data analysis, but
if the animals are considered individually, a significant decrease in
fibrinogen deposition onto PEU-SO3-0.10 is observed as compared to PEU.
This trend has been disclosed in prior art references which indicate that
platelet and fibrinogen deposition both decreased when propyl sulfonate
functionality was incorporated into PTMO-based polyurethane block
copolymers which were chain-extended with N-methyldiethanolamine.
Higher levels of ionization resulted in significant increases in fibrinogen
deposition, as shown in FIG. 8 and in Table VII. Fibrinogen deposition
onto PEU-SO3-0.15 and PEU-SO3-0.20 was higher than on PEU or the other
materials at all time points of blood exposure. Due to the inter-animal
variations, it was impossible to distinguish between these two materials.
Results from the second surgery set confirmed the highly significant
increase in fibrinogen deposition on copolymer PEU-SO3-0.20. This result
was surprising and unexpected because the platelet and fibrinogen
deposition results of the prior art indicate that the trends in the
magnitudes of platelet and fibrinogen deposition for polyurethane
ionomers, along with polyurethanes and other polymers, tend to parallel
each other. The present invention represents the first occurrence of low
platelet deposition being accompanied with unusually high fibrinogen
deposition levels in the canine ex vivo model.
Another significant difference between the behavior of the present
copolymers and prior materials is that the initial platelet deposition
rates onto PEU-SO3-0.15 and PEU-SO3-0.20 were very low, in contrast with
the polyurethane zwitterionomer and anionomer where deposition levels of
nearly 50 platelets/1000 m.sup.2 were seen after only two minutes of blood
exposure.
Scanning electron micrographs of platelets adhering to these polyurethane
surfaces showed differences in the platelet-surface interactions depend
upon the ionic content of the polymer. Platelets adherent on the
polyethylene reference material showed a tendency to spread on the
surface, and many small platelet thrombi are seen on polyethylene compared
to well-phase-separated polyurethane block copolymers (Lelah et al., in
Polymers as Biomaterials, Plenum Press. New York, 257 (1984); Grasel et
al., Biomaterials, 7, 315 (1987).
FIG. 11 shows platelets adherent on PEU at blood exposure time of 5, 15, 30
and 60 minutes. These platelets show some pseudopod extension and platelet
shape-change, but very little platelet spreading, in agreement with
previous observations on the same material.
Platelets adherent on PEU-SO3-0.10 are shown in FIG. 12 for the same blood
exposure times. In agreement with the platelet deposition profiles of FIG.
7, relatively few platelets are seen on this material as compared to PEU,
especially at 5 and 60 minutes. Although the platelet numbers are similar
to those on PEU at 15 and 30 minutes of blood exposure, platelets on
PEU-SO3-0.10 show significantly less pseudopod extension and appear much
rounder than those on PEU. The platelet morphologies observed at 15
minutes on PEU-SO3-0.10 are very similar to those observed in the prior
art on a polyurethane zwitterionomer. However, the platelets adherent at
60 minutes on this material are considerably rounder than those found on
the zwitterionomer.
The most striking scanning electron micrographs were of PEU-SO3-0.15 and
PEU-SO3-0.20, as indicated by the micrographs adherent on the latter of
these materials in FIG. 13. After 5 minutes of blood exposure, there were
virtually no adherent platelets on this material. This is in agreement
with the platelet deposition curves obtained by radiolabeling studies.
Some platelets are observed at longer exposure times, but large bare
patches are also observed. This unusual behavior has not been observed
previously in the ex vivo experiment. The adherent platelets are very
round and generally not pseudopodial, although the micrograph at 15
minutes of blood exposure shows some pseudopodia that are interacting with
other pseudopodia and platelets.
No significant fibrin formation was observed on these ionized surfaces by
scanning electron microscopy, but it should be noted that fibrin is rarely
observed in the canine ex vivo arteriovenous shunt configuration operating
at shear rates on the order of 1000 sec.sup.- 1 and above.
Although the mean platelet deposition levels for PEU-SO3-0.15 and -0.20
begin to approach those of the other polyurethanes at 60 minutes of blood
exposure, the platelet morphologies are strikingly different on the
polyurethane anionomers. When platelets are adherent on a surface, as
shown in FIG. 14b for PEU-SO3-0.15 after 30 minutes of exposure to blood,
the platelets tended to be in groups of platelets adherent to and
interacting with each other, instead of with the surface. The platelets
forming the base of the thrombus in FIG. 14b are spread over the surface.
The cause of this thrombus was most likely a dust particle or coating
imperfection or other random event of the same type often seen with other
materials.
Platelet and fibrinogen deposition profiles for the second surgery set are
shown in FIGS. 9 and 10 for PEU, PEU-SO3-0.20, and the carboxylated
analogs of the latter copolymer. The same trends in platelet and
fibrinogen deposition are observed between PEU and PEU-SO3-0.20, and in
fact the trends are more pronounced here than in the first series of
animal experiments due to minimal inter-animal variations. The actual
differences in the deposition levels between the two surgery sets were
probably due to animal-to-animal variations within each surgery set.
As the sulfonate level increases, the mean platelet deposition levels
decrease, as shown in FIG. 9. Thus, the presence of sulfonate and not the
presence of ionic species appears to affect platelet deposition onto these
polyurethanes. Similarly, fibrinogen deposition appears to be related,
almost logarithmically, to the percentage of sulfonate incorporation into
the copolymer, with the carboxylate groups appearing to have less effect.
A small effect may be indicated by the fact that fibrinogen deposition is
enhanced on PEU-SO3-0.1 COO-0.1 as compared to PEU. The same trend is not
observed for PEU-SO3-0.1 COO-0.1 as compared to PEU, or for PEU-SO3-0.1 as
compared to PEU in the first surgery set.
Because of the similarity of the ex vivo results of those polymers,
however, it is difficult to quantify the effect of carboxylate
functionality on platelet and fibrinogen deposition. The effect, however,
is not as significant as the effect of incorporating sulfonate
functionality into the polyurethane block copolymer.
I. POSSIBLE MECHANISMS OF THE SULFONATED POLYURETHANE-BLOOD INTERACTION
As previously noted, it is surprising that highly sulfonated surfaces show
little platelet adhesion and activation, and at the same time shown high
levels of fibrinogen deposition. Previously, it was generally believed
that the ability of a polymer surface to promote platelet adhesion and
activation is correlated with the amount of adsorbed or deposited
fibrinogen. The binding of fibrinogen to a surface from blood or whole
plasma is a complex process that involves competition with a number of
other plasma proteins over a short period of time. In the absence of other
proteins, the amount of adsorbed fibrinogen in a monolayer can range from
0.21 g/cm.sup.2 for side-on adsorption to 1.57 g/cm.sup.2 for end-on
adsorption. It is improbable that materials such as PEU-SO3-0.2 adsorb
fibrinogen to the exclusion of every other protein, so that some
multi-layer adsorption or absorption of fibrinogen is likely.
It is known that albumin, which is negatively charged at pH 7.4, adsorbs
more slowly to a negative-charged surface than to a positively-charged
surface. The electrokinetic effect of albumin adsorption may permit a
protein such as fibrinogen to adsorb more rapidly to a negatively-charged
surface. Conversely, it has also been found that an anionic polyurethane
selectively adsorbed albumin from competitive adsorption experiments.
However, previous studies did not report large charge-related effects on
fibrinogen adsorption behavior.
The preferential adsorption of fibrinogen to the PEU-SO3-0.20 anionomer has
been examined in in vitro adsorption studies from both heparinized and
citrated whole blood. Peak plateau levels of fibrinogen deposition on the
order of 2 or more g/cm.sup.2 were measured in both cases. In simple
fibrinogen adsorption from buffer, the same trend in fibrinogen adsorption
was detected.
It is possible that fibrinogen molecules are being absorbed to some extent
in the water-containing hydrogels. However, there still is a reduced level
of platelet attachment and activation at the surface. An explanation of
these trends may be related to the configuration and/or conformation of
the adsorbed fibrinogen that is on the surface. Prior studies have
examined the differences in platelet retention and activation on polyalkyl
methacrylates which had similar fibrinogen binding characteristics. It was
found that differences in binding affinities of adsorbed fibrinogen
molecules for fibrinogen antibody, as opposed to the total number of
adsorbed fibrinogen molecules, correlated with "platelet reactivity".
Further studies have indicated that the conformation of adsorbed fibrinogen
molecules, as opposed to differences in the orientation of the adsorbed
fibrinogen, is the primary determinant of the anti-fibrinogen binding to
the fibrinogen adsorbed on these materials. All of the prior art appears
to lead to the conclusion that fibrinogen molecules bound to a surface in
an undistorted, "native" conformation are required for platelet activation
by surfaces to occur. In the polymers of the present invention, however,
the ionic surfaces may be inducing a conformational change in the
fibrinogen molecule which may reduce or prevent platelet attachment or
activation.
As demonstrated herein, the incorporation of sulfonate and carboxylate
groups into a polyurethane block copolymer exerts an effect on bulk
properties, surface chemistry, and blood compatibility as measured in an
acute canine ex vivo blood-contacting experiment.
Bulk physical property testing including differential scanning calorimetry,
dynamic mechanical testing, and infrared spectroscopy indicate variations
in bulk morphology as the ionic content is changed. Initially, at low
levels of ion incorporation, phase separation decreases as the hard
segments become more disordered, but phase separation improves as the
ionic content is further raised. The water sensitivity of the present
ionic polymers may limit their application in certain environments, and
the high-temperature performance appears poorer for the anionomers than
for the base material.
ESCA data collected in vacuo indicates surface soft segment enrichment and
nearly identical surface chemistry for all of the present polymers
materials, but contact angle/wettability data show major differences for
these polymers, with wettability increasing with ionic content.
Blood compatibility data clearly indicates that as the level of sulfonate
incorporation is increased, platelet attachment and platelet spreading and
activation decrease substantially. The unusual phenomenon of increased
fibrinogen deposition on the sulfonated polymers, when compared to the
uncharged base polymer, indicates conformational changes in the fibrinogen
molecules upon adsorption which renders the surface
non-platelet-activating. Carboxylate incorporation into the copolymers of
this invention has an effect in increasing fibrinogen deposition, but the
effect of sulfonate incorporation is more pronounced.
While the present invention has been described with reference to particular
embodiments, it will be understood that various changes and modifications
can be made without departing from the spirit of the invention.
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